【摘要】：目前,全世界大約有數億人暴露在高砷環(huán)境中,中國是受砷危害的最為嚴重的國家之一,地方性砷中毒在我國發(fā)現時間短、病情重、病區(qū)范圍大,而且暴露在高砷水平下的人口還在繼續(xù)擴大。 由于砷在體內作用機制復雜,其慢性毒性作用及致病機理仍然不是很清楚,對砷的發(fā)病機理研究至今仍沒有取得突破性的進展,近幾年研究表明,砷中毒主要導致血管病變,特別是對血管內皮的損傷。血管內皮是覆蓋在血管內膜表層,在血管損傷的自我修復過程中起決定作用。目前研究已確切表明,地砷病不但可以造成各系統疾病,長期接觸砷,還可導致各種癌癥,如膀胱癌、肺癌、肝癌、乳腺癌等。迄今為止,砷的致癌機制仍不清楚�；谝陨显蛭覀儜秒u胚絨毛尿囊膜(CAM)血管新生模型作為亞砷酸鈉對血管增殖影響體內研究模型；以人臍靜脈內皮細胞(HUV-EC)作為亞砷酸鈉對血管增殖的體外研究模型,觀察亞砷酸鈉對血管增殖毒性效應；以小鼠乳腺上皮細胞(NMuMG)為研究對象,研究砷的誘導EMT作用,以期為砷的致癌機制提供理論依據。經研究我們發(fā)現,NaAsO2對體內外血管增殖均有抑制作用,這可能是砷化物中毒引起血管疾病的發(fā)生機制之一。在應用小鼠乳腺上皮細胞(NMuMG)作為研究砷誘導EMT模型之前,我們先觀察了砷對NMuMG的直接毒性效應。我們首次發(fā)現NaAsO2能夠改變細胞形態(tài),抑制細胞增殖,引起細胞凋亡,且通過抑制c-Myc表達,促進P21表達來實現的。為了研究砷誘導EMT,我們先建立了TGF-β介導的EMT模型,接著我們首次成功的通過NaAsO2介導NMuMG發(fā)生EMT,同時我們還進一步發(fā)現砷是通過HMGA2途徑誘導EMT。 上述研究結果為地砷病的血管損傷機制提供了進一步的理論依據,同時對于砷的致癌機制提供新的理論基礎,砷正是通過引起正常細胞的發(fā)生上皮向間充質細胞的轉化而引起癌癥的。
[Abstract]:At present, there are hundreds of millions of people in the world exposed to high arsenic environment. China is one of the countries most seriously affected by arsenic. Endemic arsenic poisoning is found in China for a short time, the disease is serious, and the scope of the disease area is large. And the population exposed to high arsenic levels continues to grow. Because of the complex mechanism of arsenic acting in vivo, the chronic toxicity and pathogenesis of arsenic are still unclear. So far, no breakthrough has been made in the study of the pathogenesis of arsenic. In recent years, it has been shown that arsenic poisoning mainly leads to vascular disease. Especially the injury of vascular endothelium. Vascular endothelium is covered in the intimal layer and plays a decisive role in the self-repair of vascular injury. At present, it has been proved that the disease can not only cause systemic diseases, long-term exposure to arsenic, but also lead to various cancers, such as bladder cancer, lung cancer, liver cancer, breast cancer and so on. To date, the carcinogenic mechanism of arsenic remains unclear. For the above reasons, we used the chicken chorioallantoic membrane (CAM) angiogenesis model as an in vivo model to study the effect of sodium arsenite on vascular proliferation. Human umbilical vein endothelial cells (HUV-EC) were used as an in vitro model to study the effects of sodium arsenite on the proliferation of blood vessels. In order to provide theoretical basis for the carcinogenic mechanism of arsenic, the EMT induced by arsenic in mouse mammary epithelial cells (NMuMG) was studied. We found that NaAsO2 can inhibit the proliferation of blood vessels in vivo and in vitro, which may be one of the mechanisms of vascular diseases caused by arsenide poisoning. Before using mouse mammary epithelial cell (NMuMG) as the model of arsenic induced EMT, we observed the direct toxicity of arsenic to NMuMG. We found for the first time that NaAsO2 could change cell morphology, inhibit cell proliferation and induce apoptosis, which was achieved by inhibiting the expression of c-Myc and promoting the expression of P21. In order to study arsenic induced EMT, we first established TGF- 尾 -mediated EMT model, then we successfully induced NMuMG EMT, by NaAsO2 for the first time, and we further found that arsenic induces EMT. via HMGA2 pathway. These results provide a further theoretical basis for the vascular injury mechanism of arsenic disease, and provide a new theoretical basis for the carcinogenesis mechanism of arsenic. Arsenic causes cancer by causing the transformation of normal cells from epithelium to mesenchymal cells.
【學位授予單位】：吉林大學
【學位級別】：博士
【學位授予年份】：2011
【分類號】：R363

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本文編號：2338180